PSF functions as a repressor of hypoxia-induced angiogenesis by promoting mitochondrial function.
PSF functions as a repressor of hypoxia-induced angiogenesis by promoting mitochondrial function.
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DOI：
10.1186/s12964-020-00684-w
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发表时间：
2021-02-11
期刊：
影响因子：
--
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Dong L;Li W;Lin T;Liu B;Hong Y;Zhang X;Li X
异常的新生血管形成是失明的最常见原因，并且缺氧改变组织代谢、功能和形态。HIF-1α是VEGF的转录激活因子，具有复杂的核转位和激活机制，但其信号终止机制尚不清楚。本研究通过体内和体外靶向HIF-1α研究了多聚嘧啶片段结合蛋白相关剪接因子（polypyrimidine tract-binding protein-associated splicing factor，PSF）在细胞能量产生、迁移和增殖中的作用。将年轻的C57/BL 6 J小鼠保持在高氧环境中，然后保持在室内空气中，导致氧诱导的视网膜病变。将氧诱导视网膜病变（OIR）动物随机分为3组：OIR组、OIR +载体组（用rAAV载体处理OIR幼仔）和OIR + PSF组（用rAAV-PSF处理OIR幼仔）。将C57/BL 6 J小鼠作为对照，并暴露于恒定的常氧条件。这些动物被处死，它们的瞳孔被用于随后的实验。采用Seahorse XFe 96通量分析仪分析代谢谱，同时定量分析OCR和胞外酸化率。PSF改善了氧诱导视网膜病变小鼠的视网膜新生血管形成，纠正了VEGF的异常表达，并减少了Vldlr − / −小鼠的视网膜内新生血管形成。PSF可重编程线粒体生物能学，抑制缺氧后内皮细胞的转换，提示其参与病理性血管生成;异位PSF表达可通过将Hakai募集到PSF/HIF-1α复合物中，抑制缺氧诱导的细胞核内HIF-1 α的活化。PSF基因敲除增加了缺氧刺激的HIF-1α反应。这些缺氧依赖性过程可能在细胞代谢、迁移和增殖中起重要作用。因此，PSF是新生血管相关眼病的潜在治疗靶点。这是第一项研究表明，PSF通过招募Hakai抑制HIF-1α，调节线粒体氧化和糖酵解，并下调缺氧条件下VEGF的表达。我们提出了一种新的HIF-1 α/Hakai调节机制，可能在眼病新生血管的发病机制中发挥重要作用。 低氧条件下PSF-Hakai-HIF-1α信号通路的研究示意图显示PSF-Hakai-HIF-1α信号通路。在缺氧条件下，PSF-Hakai复合物通过调节HIF-1α信号通路，最终抑制下游靶基因VEGF、细胞代谢和血管生成。视频摘要：材料和方法的详细信息。
Abnormal neovascularization is the most common cause of blindness, and hypoxia alters tissue metabolism, function, and morphology. HIF-1α, the transcriptional activator of VEGF, has intricate mechanisms of nuclear translocation and activation, but its signal termination mechanisms remain unclear. We investigated the role of polypyrimidine tract-binding protein-associated splicing factor (PSF) in cellular energy production, migration, and proliferation by targeting HIF-1α in vivo and in vitro PSF plasmids were transfected with liposome 2000 transfection reagent. Young C57/BL6J mice were kept in a hyperoxia environment, followed by indoor air, resulting in oxygen-induced retinopathy. Oxygen-induced retinopathy (OIR) animals were randomly divided into three groups: OIR group, OIR + vector group (OIR cubs treated with rAAV vector) and OIR + PSF group (OIR cubs treated with rAAV-PSF). Age-matched C57/BL6J mice were used as controls and exposed to constant normoxic conditions. The animals were executed and their pupils were subjected to subsequent experiments. The metabolic spectrum was analyzed by Seahorse XFe96 flux analyzer, and OCR and extracellular acidification rate were quantified at the same time. PSF ameliorated retinal neovascularization and corrected abnormal VEGF expression in mice with oxygen-induced retinopathy and reduced intra-retinal neovascularization in Vldlr − / − mice. PSF reprogrammed mitochondrial bioenergetics and inhibited the transition of endothelial cells after hypoxia, suggesting its involvement in pathological angiogenesis.Ectopic PSF expression inhibited hypoxia-induced HIF-1α activation in the nucleus by recruiting Hakai to the PSF/HIF-1α complex, causing HIF-1α inhibition. PSF knockdown increased hypoxia-stimulated HIF-1α reactions. These hypoxia-dependent processes may play a vital role in cell metabolism, migration, and proliferation. Thus, PSF is a potential treatment target in neovascularization-associated ophthalmopathy. This is the first study showing that PSF inhibits HIF-1α via recruitment of Hakai, modulates mitochondrial oxidation and glycolysis, and downregulates VEGF expression under hypoxia. We propose a new HIF-1 α/Hakai regulatory mechanism that may play a vital role in the pathogenesis of neovascularization in ophthalmopathy. PSF-Hakai–HIF-1α signaling pathway under hypoxia condition. Schematic diagram showing that the PSF-Hakai–HIF-1α signaling pathway. Under hypoxia condition, PSF-Hakai complex regulate HIF-1α signaling, thus inhibiting downstream target gene VEGF, cell metabolism and angiogenesis eventually. Video Abstract: Detailed information of Materials and Methods.
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影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
3.3
作者：
Figueroa, Angelica;Kotani, Hirokazu;Fujita, Yasuyuki
通讯作者：
Fujita, Yasuyuki
影响因子：
2.5
作者：
Chen, Xi;Yao, Jia-Mei;Zhong, Guang-Wei
通讯作者：
Zhong, Guang-Wei
影响因子：
5.2
作者：
Shao, Yan;Chen, Jianglei;Ma, Jian-Xing
通讯作者：
Ma, Jian-Xing
影响因子：
5.4
作者：
Liu, Zi;Wu, Yuqing;Ma, Liang
通讯作者：
Ma, Liang